The invention relates to N-formylation of certain amino carboxylic compounds. An amino acid carboxylic alkali metal salt, e.g., the disodium salt of aspartic acid, is reacted with an alkyl formate to convert the amino group to a N-formyl group, --NH--CHO. The alkali metal salts of N-formyl-L-aspartic acid are believed novel. In one embodiment, the alkyl formate is formed in situ from carbon monoxide and an alkanol. In another embodiment, the alkyl formate is added to the reaction. With the amine group protected (by the N-formylation) the compound can then be used in conventional dipeptide synthesis or in other chemical or enzymatic reactions. The protecting formyl group may be removed by mild hydrolysis.
N-formylation of amino carboxylic acids is not new and a number of reagents have been employed to protect the amine group in this manner. However, the prior art processes are complex, expensive and/or do not provide adequate yields. For example: L-phenylalanine has been N-formylated by treating its sodium salt with chloral, Chem. Abs. 102(11):96080z. D-phenylalanine, glycine, valine and glutamic acid have been N-formylated with HCO.sub.2.SO.sub.3.Na, Chem. Abs. 85(1):6043t. Acetic anhydride has been added to amino acid in formic acid, Sheehan et al., J. Am. Chem. Soc., Vol. 80, p. 1154 (1958); Gensler et al., J. Org. Chem., Vol. 21, p. 336 (1956). Benzyl esters of amino acid derivatives can be N-formylated with formic acid in the presence of N,N'-dicyclohexylcarbodiimide, Thomas, Tetrah. Let. 335 (1967). N-formylation of t-butylamine with ethyl formate has been reported in yields of 29.4 to 84%, Moffatt et al., J. Org. Chem., Vol. 27, p. 4058 (1962).
Both primary and secondary amines react with carbon monoxide in the presence of various catalysts to yield N-formyl amines. For example, formamide is prepared commercially by one of the following two processes: (1) by direct synthesis, reacting ammonia and carbon monoxide in methanolic sodium methoxide in the presence of catalysts; or (2) by a two-stage synthesis, first reacting carbon monoxide and methanol in the presence of catalytic sodium methoxide to form methyl formate, then treating the methyl formate with liquid or gaseous ammonia, Kirk-Othmer, Enc. Chem. Tech., 3rd Ed., Vol. 11, pp. 258-60 (1980).